Summary

In this study the investigators want to find out about the effects of this drug in women
with metastatic breast cancer. The study has two major parts; dose escalation and dose
expansion. In the first part or dose escalation, subjects will be treated at the lowest dose
effective in men: 300 mg two times daily. Orteronel (TAK-700) will be increased to reach the
highest dose tolerated in men: 400 mg two times daily. This part of the study is designed to
see if female subjects can safely tolerate orteronel (TAK-700), and to measure the changes
in estrogens and androgens at different levels of TAK-700.

In the second part of the study (dose expansion), seven women will be treated with the dose
identified in the first part of the study as being safest and most effective. In this part
of the study, the investigators want to see if orteronel (TAK-700) will routinely and
significantly decrease the estrogen levels at the dose which will be used for any future
studies.

dose is dependant on dose escalation timepoint and dose expansion cohort dose will be the RP2D determined based on the dose escalation cohort final dose recommendation

Primary Outcomes

Measure

Number of Participants with Adverse Events as a Measure of Safety and Tolerability as a way to determine the recommended phase 2 dose.

time frame:
one year

decrease in serum estradiol level

time frame:
one year

Secondary Outcomes

Measure

Overall Response Rate

time frame:
one year

Number of Participants with Adverse Events as a Measure of Safety and Tolerability

time frame:
one year

pharmacodynamic activity of orteronel with steroid and endocrine levels

time frame:
two years

response rate, progression-free survival and time to progression

time frame:
2 years

Eligibility Criteria

Female participants at least 18 years old.

Inclusion Criteria:
- Voluntary written informed consent
- Patients 18 years or older
- Screening clinical laboratory values as specified below:
- Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be the
upper limit of normal (ULN).
- Total bilirubin ≤ 1.5 x ULN.
- Serum creatinine ≤ 1.5 × ULN or Estimated creatinine clearance using the
Cockcroft-Gault formula must be greater than 50 mL/minute
- Absolute neutrophil count (ANC) greater than 1000/L and platelet count greater than
75,000/L.
- Serum potassium levels must be within institutional normal limits.
- Serum magnesium and phosphorous levels must be ≥ the institutional lower limit of
normal.
- Screening calculated ejection fraction greater than or equal to the institutional
upper limit of normal
- Patients must have histologically confirmed breast cancer that is Metastatic OR
Incurable and locally advanced
- Patients must have histologically confirmed HR+ breast cancer.
- Patients must have measureable or evaluable disease
- ECOG performance status <2 (Karnofsky >60%)
- Patients must be postmenopausal women.
Inclusion Criteria for Dose Expansion Cohort:
- All of the criteria listed in above in addition to those below:
- Patients must have measurable disease.
- Patients may not have received more than 1 prior line of endocrine therapy in the
metastatic setting.
- Patients may not have received any cytotoxic chemotherapy for treatment in the
metastatic setting.
Exclusion Criteria:
- Exclusion Criteria for Dose Escalation Cohort
- Patients meeting any of the following exclusion criteria are not to be enrolled in
the study.
- Patients who have not discontinued all prior medical therapy for breast cancer (with
the exception of bisphosphonates or denosumab) at least 28 days prior to first dose
of orteronel.
- Patients who are taking any form of other exogenous hormonal therapy within 28 days
prior to first dose of orteronel.
- Patients should not have received radiotherapy within 14 days prior to the first dose
of orteronel.
- Patients should have recovered to baseline or < grade 1 for all-prior treatment
related toxicities.
- EKG abnormalities of:
- Q-wave infarction, unless identified 6 or more months prior to screening QTc
interval > 470 msec, the upper limit of normal for women.
- Known hypersensitivity to compounds related to orteronel or to orteronel
excipients.
- Uncontrolled hypertension despite appropriate medical therapy
- Known active chronic hepatitis B or C, life-threatening illness unrelated to
cancer, or any serious medical or psychiatric illness that could, in the
investigator's opinion, potentially interfere with participation in this study.
- Likely inability to comply with the protocol or cooperate fully with the investigator
and site personnel.
- Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI
absorption or tolerance of orteronel, including difficulty or inability to swallow
tablets.
- Patients with known endocrine disorders including, but not limited to, Cushing's, or
Addison's disease.
- Patients with known brain metastases are excluded unless they have had definitive
treatment (e.g. whole brain radiotherapy or surgery or stereotactic radiation) for
brain metastases with evidence of stable/improved disease on repeat imaging following
definitive treatment.
- Patients on medications with the potential for significant interaction with
orteronel.
- Patients with serious medical illness
- Patients with an estimated life expectancy of less than 3 months as determined by the
treating physician.
- Prior therapy with abiraterone, or aminoglutethimide.
Exclusion Criteria for Dose Expansion Cohort Patients meeting any of the following
exclusion criteria are not to be enrolled in the study:
- They are ineligible by virtue of meeting any exclusion criteria above. Patients with
known brain metastases will be excluded from this portion of the clinical trial
(which will assess PFS and TTP) because of their relatively poor overall prognosis.
- Patients with HER2+ breast cancer are also excluded from this portion of the study as
HER2-targeted therapy would generally be considered appropriate for the HER2+ patient
population meeting the entry criteria for the dose expansion cohort.
- They have received treatment with orteronel or another lyase inhibitor in the past.
- Diagnosed or treated for another malignancy within 2 years of enrollment, with the
exception of in situ malignancies.